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Klinefelter syndrome

Friday 13 June 2003

Definition: Klinefelter syndrome is a well documented abnormality of sex differentiation, with an incidence of 1 in 600 newborn males.

Klinefelter syndrome is characterized by a 47,XXY or a mosaic karyotype and clinical findings of hypergonadotrophic hypogonadism, small testes, infertility, reduced body hair, gynecomastia, and tall stature.

Other conditions like venous disease, autoimmune disorders, mild neurobehavioral deficit, diabetes mellitus, sexual precocity, and osteoporosis may also affect these patients.

Klinefelter syndrome is best defined as male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes. It is one of the most frequent forms of genetic disease involving the sex chromosomes as well as one of the most common causes of hypogonadism in the male.

The incidence of this condition is approximately 1 in 500 live male births. It can rarely be diagnosed before puberty, particularly because the testicular abnormality does not develop before early puberty.

Most patients have a distinctive body habitus with an increase in length between the soles and the pubic bone, which creates the appearance of an elongated body.

Also characteristic are eunuchoid body habitus with abnormally long legs; small atrophic testes often associated with a small penis; and lack of such secondary male characteristics as deep voice, beard, and male distribution of pubic hair. Gynecomastia may be present. The mean IQ is somewhat lower than normal, but mental retardation is uncommon.

This typical pattern is not seen in all cases, the only consistent finding being hypogonadism. Plasma gonadotropin levels, particularly follicle-stimulating hormone, are consistently elevated, whereas testosterone levels are variably reduced.

Mean plasma estradiol levels are elevated by an as yet unknown mechanism. The ratio of estrogens and testosterone determines the degree of feminization in individual cases.

Klinefelter syndrome is the principal cause of reduced spermatogenesis and male infertility. In some patients, the testicular tubules are totally atrophied and replaced by pink, hyaline, collagenous ghosts. In others, apparently normal tubules are interspersed with atrophic tubules.

In some patients, all tubules are primitive and appear embryonic, consisting of cords of cells that never developed a lumen or progressed to mature spermatogenesis. Leydig cells appear prominent, owing to the atrophy and crowding of tubules.

Patients with Klinefelter syndrome have several associated disorders such as breast cancer (20 times more common than in normal males), extragonadal germ cell tumors, and autoimmune diseases such as systemic lupus erythematosus (presumably related to low testosterone and high estrogen levels).

The classic pattern of Klinefelter syndrome is associated with a 47,XXY karyotype (82% of cases). This complement results from nondisjunction during the meiotic divisions in one of the parents.

Maternal nondisjunction at the first meiotic division accounts for a little more than half of the cases. Most of the remaining result from nondisjunction during the first paternal meiotic division.

There is no phenotypic difference between those who receive the extra X chromosome from their father and those who receive it from their mother. Maternal age is increased in the cases associated with errors in oogenesis. In addition to this classic karyotype, approximately 15% of patients with Klinefelter syndrome have been found to have a variety of mosaic patterns, most of them being 46,XY/47,XXY.

Other patterns are 47,XXY/48,XXXY and variations on this theme. Rare individuals have also been found to possess 48,XXXY or 49,XXXXY karyotypes.

Such polysomic X individuals have further physical abnormalities, including cryptorchidism, hypospadias, more severe hypoplasia of the testes, and skeletal changes, such as prognathism and radioulnar synostosis.

Tumor predisposition

Different malignancies such as breast cancer, testicular tumors, leukemia, and lymphomas occur in 1%-2% of the cases. Klinefelter syndrome has been associated with other malignancies such as extragonadal germ cell tumors.

- Extragonadal germ cell tumors (16564924)
- breast cancer
- testicular tumors
- leukemias
- lymphomas


- Robbins. Pathologic basis of disease.

- Extragonadal germ cell tumors are often associated with Klinefelter syndrome. Aguirre D, Nieto K, Lazos M, Peña YR, Palma I, Kofman-Alfaro S, Queipo G. Hum Pathol. 2006 Apr;37(4):477-80. PMID: 16564924